Increasing evidence suggests that human cytomegalovirus (HCMV) contributes to the development of both restenosis and atherosclerosis. Although one potential mechanism could reside in the known capacity of HCMV to enhance cellular proliferation, which could lead to the smooth muscle cell (SMC) accumulation characteristic of both disease processes, recently it has been also demonstrated that HCMV inhibits apoptosis. This provides another mechanism whereby HCMV might contribute to developing restenotic and atherosclerotic lesions. Although CMV infection leads to the coexpression of IE1-72 and IE2-84, we have attempted to dissect the individual role of the proteins on p53-dependent and p53-independent pathways using recombinant adenoviruses to transiently overexpress separately each of the immediate early gene products. We found that IE2-84 protects human coronary artery SMCs (HCSMCs) from the p53-dependent apoptosis induced by doxorubicin or overexpression of wild-type p53. Similary, IE2-84 protects Saos-2 cells (p53-null) from apoptosis induced by serum starvation. In contrast, IE1-72 potentiates p53-dependent apoptosis in HCSMCs. However, in Saos-2 cells, similar to IE2-84, IE1-72 is protective. We postulate that IE1-72, through its capacity to drive its host cell to "inappropriately" proliferate, stimulates p53-mediated apoptosis. However, in the presence of IE2-84, which inhibits apoptosis, these two proteins act in concert and cause SMC accumulation both by driving the cell to proliferate and by inhibiting apoptosis. These data, taken together with those of other studies, provide mechanistic evidence compatible for a role of HCMV in both restenosis and atherosclerosis.